Yersinia pestis, the causative agent of plague, represents the most feared biological warfare agent, as individuals infected via the respiratory route not only succumb to the disease within 72 hours, but also transmit Y. pestis to unexposed populations. Thus, the effect of a biological warfare attack with Y. pestis will be amplified by the exponential spread of the resulting epidemic. Once an individual is infected with an aerosol of Y. pestis and once clinical signs become apparent, antibiotic therapy is no longer effective and vaccination of the general population appears to be the only effective means of prevention and protection against plague. There is at present no effective commercially available plague vaccine. Protective immunity to Y. pestis infection can be achieved either by injecting live attenuated plague bacilli, killed bacterial suspensions, or purified proteins ("protective antigens") into experimental animals. The latter cause minimal side effects and thus are preferred for immunization. Examples are the capsular antigen fraction 1 (Caf1) and the low-calcium-response protein V (LcrV or V antigen), however attempts to exploit Caf1 and LcrV as a subunit vaccine may be futile. Major concerns are that the Caf1 surface antigen is dispensable for the pathogenesis of Y. pestis infections and that LcrV is not only a suppressor of inflammation and immunity in humans but also displays antigenic variation. These circumstances will either diminish the success of Caf1-LcrV vaccines or allow biological warfare organizations to generate plague strains capable of escaping immune protection, thereby abrogating the defense effort of vaccine research. This proposal represents an interdisciplinary and multi-institutional approach to develop new plague vaccines and to establish a rational understanding of protective immunity against plague. Robert Brubaker (Michigan State University) and Olaf Schneewind (University of Chicago) examine the pathogenesis of Y. pestis infections, the development of plague vaccines and the Yersinia type III secretion mechanism. John Xu (University of Illinois, Urbana-Champaign) and Averil Ma (University of Chicago) study host immune functions that control Yersinia infections and Natalia Maltsev (Argonne National Laboratory) applies bioinformatic approaches to the analysis of Y. pestis genome sequences. This group of investigators will identify surface protein antigens of Y. pestis that are essential for the pathogenesis of plague.